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Keeping clinical trials on track is a challenge to doctors, nurses: Clues to Cancer

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Dr. Smitha Krishnamurthi discusses a patient with Dr. Afshin Dowlati during a Phase 1 clinical trial meeting at University Hospitals on March 8. Doctors, nurses and case managers meet to discuss the condition of patients participating in the trial.
(Lynn Ischay, The Plain Dealer)

We have to appreciate the unique [calculation] that patients go through in determining whether a clinical trial is right for them. -- Dr. Neal Meropol

CLEVELAND, Ohio — When Dr. Neal Meropol joined University Hospitals in 2009, he immediately started working on one of the biggest tasks set before him: cutting in half the time to move a cancer clinical trial from initialreview to enrolling patients.

Meropol, chief of the division of hematology/oncology at UH and associate director for clinical programs at UH Seidman Cancer Center, also worked to increase the number of clinical trials, particularly Phase 1 trials, at Seidman.

To that end, he began working with the teams of physicians and nurses who focus on studies for specific types of cancerto make sure that thetrials reflect the needs of UH's patients.

The discussion revolved around designing trials to answer scientific questions more quickly; the potential for noninvasive tests, beyond the CT scan, that can predict which patients will benefit from particular treatments and can monitor their progress; and recruiting and retaining patients.

Because the organization's membership includes a large number of scientists who are not directly involved in clinical trials once they open, Meropol said he wanted to approach the discussion from the patient's point of view.

"When faced with the opportunity [of a trial], for them it's a treatment decision," he said. "We have to appreciate the unique [calculation] thatpatients go through in determining whether a clinical trial is right for them."

The Phase 1 team at UH continues to face other challenges:

• Staffing. The program is designed to operate with four clinical trial nurse coordinators, but currently one position is open. It's not easy to find a nurse with the right blend of oncology and research experience, says Dr. Afshin Dowlati, director of the Developmental Therapeutics Program at Case Comprehensive Cancer Center and director of Seidman's Center for Cancer Drug Development.

• The structure of study protocols. In a standard "3-plus-3" design, a maximum of three patients are enrolled at a site during the first month. If no one experiences any drug side effects in the first few weeks, three more patients can be added at a higher dose, and so on until an average of four or five patient groups, or cohorts, have gone through the study. Another type of design treats just one patient, with data on the drug effects analyzed in real time. Those "rapid escalation" or "accelerated dose escalation" designs are faster-paced but lack the opportunity for gathering in-depth information on how the body reacts to the drugs.

• Patient -- and physician -- awareness and education. Sometimes it takes months to find the right patient to enroll in a clinical trial. Last summer, Seidman was the only one of six sites in the country that was ready to open a Phase 1 trial testing an older, FDA-approved drug in a new patient population: adults who were in remission from acute myeloid leukemia, or AML. But because the pool of patients who qualified -- the AML patient must have previously undergone a bone-marrow or cord-blood transplant -- was tiny, the first patient wasn't identified, successfully screened and enrolled until mid-October.

Staffing, efficiency and progress

The effort to raise awareness about cancer clinical trials never stops. It's crucial for the program's existence.

In 2011, Dowlati created the position of research protocol coordinator at Seidman to oversee the patient waiting list and lessen the workload of the research study coordinators, who had been splitting the duties. Dowlati wanted to streamline the referral process to make it easier for a patient to get in the pipeline.

He added Angela Hughes as the newest Phase 1 team member as part of a larger effort to educate physicians, both at Seidman and at other hospitals, about which patients they could refer. A nurse by training, Hughes previously coordinated studies forhead and neck cancer and geriatric oncology at UH.

The physicians who regularly attend the Phase 1 meeting may have a specific trial in mind for someone. But nothing is definite until Hughes and the research study coordinators review a person's diagnosis and medical status to verify him or her as a potential candidate.

Hughes communicates regularly with pharmaceutical-company sponsors so that she has an idea of what sorts of studies at UH might be available for patients down the road.

Some trials take only patients with certain types of cancers. Other trials disqualify those with kidney or liver problems. Some exclude patients because they have previously had certain types of treatment.

For some patients, that perfect match is never realized.

"I sometimes feel like I am letting [them] down, that I cannot get them on a trial," Hughes said.

It's important to enroll eligible patients as quickly as possible in a trial, not only to give them potential treatment options, but to ensure that the trial remains open.

In the past two years, the National Cancer Institute has begun closely monitoring all trials it sponsors, and notifying investigators if their trial is in danger of being shut down.

Every six months, Case Comprehensive, a collaboration of institutions based at Case Western Reserve University, reviews the enrollment of every clinical trial in its portfolio. If the trial is not on target with its enrollment goals and the projected completion date, the principal investigator must justify why the trial should remain open.

It's all part of an effort nationwide to ensure that new studies are on pace with emerging research.

"Ideally you want [the trials] to enroll quickly and close quickly, and write it up while the science is still fresh and interesting," said Dr. Smitha Krishnamurthi, medical director for the Clinical Trials Unit at Seidman and the No. 2 person, behind Dowlati, on the Phase 1 team.

"It's been shown that if a study doesn't [enroll] well within the first four months of opening, [that's a predictor] that it's not going to meet its accrual goal," said Krishnamurthi, an oncologist specializing in colorectal and gastrointestinal cancer.

The process may be frustrating, she said, but, "You need this research to spare people from drugs that aren't working."

Clues to Cancer: Patients, doctors on road to discovery

For 10 months, Plain Dealer reporter Angela Townsend and photographer Lynn Ischay followed 9 patients through their journey as study participants in Phase 1 trials at University Hospitals. We tell their stories here.

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